Anandamide and 2-arachidonoylglycerol differentially modulate autistic-like traits in a genetic model of autism based on FMR1 deletion in rats

Autism spectrum disorder (ASD) has a multifactorial etiology. Major efforts are underway to understand the neurobiological bases of ASD and to develop efficacious treatment strategies. Recently, the use of cannabinoid compounds in children with neurodevelopmental disorders including ASD has received increasing attention. Beyond anecdotal reports of efficacy, however, there is limited current evidence supporting such an intervention and the clinical studies currently available have intrinsic limitations that make the interpretation of the findings challenging. Furthermore, as the mechanisms underlying the beneficial effects of cannabinoid compounds in neurodevelopmental disorders are still largely unknown, the use of drugs targeting the endocannabinoid system remains controversial. Here, we studied the role of endocannabinoid neurotransmission in the autistic-like traits displayed by the recently validated Fmr1-^Δexon 8 rat model of autism. Fmr1-^Δexon 8 rats showed reduced anandamide levels in the hippocampus and increased 2-arachidonoylglycerol (2-AG) content in the amygdala. Systemic and intra-hippocampal potentiation of anandamide tone through administration of the anandamide hydrolysis inhibitor URB597 ameliorated the cognitive deficits displayed by Fmr1-^Δexon 8 rats along development, as assessed through the novel object and social discrimination tasks. Moreover, blockade of amygdalar 2-AG signaling through intra-amygdala administration of the CB1 receptor antagonist SR141716A prevented the altered sociability displayed by Fmr1-^Δexon 8 rats. These findings demonstrate that anandamide and 2-AG differentially modulate specific autistic-like traits in Fmr1-^Δexon 8 rats in a brain region-specific manner, suggesting that fine changes in endocannabinoid mechanisms contribute to ASD-related behavioral phenotypes.